Microglia contribute to social behavioral adaptation to chronic stress

Microglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute to adaptive response of the brain and behavior toward stress using a mild and adaptive stress model - chronic restraint stress (CRS) - with wild type (WT) and CX3CR1-GFP (CX3CR1[G]) mice and human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety and depressive-like behaviors, but instead strengthened social dominance and short-term spatial learning in WT mice. Compared to WT and CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate in social interaction before and after CRS. Microglia in WT mice underwent a series of region-specific changes involving their phagocytosis of presynaptic vesicular glutamate transporter 2 protein, contacts with synaptic elements, CD206(+)microglial proportion, and gene expressions such as Cx3cr1. By contrast, CX3CR1-deficient microglia showed decreased CD206(+) while increased MHCII+ subpopulations and hypo-ramification in the hippocampus, as well as sensitized polarization and morphological change in response to CRS. Furthermore, CD206(+) microglial abundancy was positively correlated with social dominancy and microglial ramification in CX3CR1-GFP mice. Moreover, CX3CR1 mRNA level was reduced in CRS-treated mouse brains and showed a smaller interactome with other brain genes in the dorsal-lateral prefrontal cortices of patients with schizophrenia. Our findings overall highlight microglia and its receptor CX3CR1 as key contributors in regulation of social behavioral adaptation to chronic stress.Peer reviewe

Association of brain immune genes with social behavior of inbred mouse strains

Background: Social deficit is one of the core symptoms of neuropsychiatric diseases, in which immune genes play an important role. Although a few immune genes have been shown to regulate social and emotional behaviors, how immune gene network(s) may jointly regulate sociability has not been investigated so far. Methods: To decipher the potential immune-mediated mechanisms underlying social behavior, we first studied the brain microarray data of eight inbred mouse strains with known variations in social behavior and retrieved the differentially expressed immune genes. We then made a protein-protein interaction analysis of them to find the major networks and explored the potential association of these genes with the behavior and brain morphology in the mouse phenome database. To validate the expression and function of the candidate immune genes, we selected the C57BL/6 J and DBA/2 J strains among the eight inbred strains, compared their social behaviors in resident-intruder and 3-chambered social tests and the mRNA levels of these genes, and analyzed the correlations of these genes with the social behaviors. Results: A group of immune genes were differentially expressed in the brains of these mouse strains. The representative C57BL/6 J and DBA/2 J strains displayed significant differences in social behaviors, DBA/2 J mice being less active in social dominance and social interaction than C57BL/6 J mice. The mRNA levels of H2-d1 in the prefrontal cortex, hippocampus, and hypothalamus and C1qb in the hippocampus of the DBA/2 J strain were significantly down-regulated as compared to those in the C57BL/6 J strain. In contrast, Polr3b in the hippocampus and Tnfsf13b in the prefrontal cortex of the DBA/2 J strain were up-regulated. Furthermore, C1qb, Cx3cl1, H2-d1, H2-k1, Polr3b, and Tnfsf13b were predicted to be associated with various behavioral and brain morphological features across the eight inbred strains. Importantly, the C1qb mRNA level was confirmed to be significantly correlated with the sociability in DBA/2 J but not in C57BL/6 J mice. Conclusions: Our study provided evidence on the association of immune gene network(s) with the brain development and behavior in animals and revealed neurobiological functions of novel brain immune genes that may contribute to social deficiency in animal models of neuropsychiatric disorders.Peer reviewe

Low-Molecular Weight Protamine Overcomes Chondroitin Sulfate Inhibition of Neural Regeneration

Protamine is an arginine-rich peptide that replaces histones in the DNA-protein complex during spermatogenesis. Protamine is clinically used in cardiopulmonary bypass surgery to neutralize the effects of heparin that is required during the treatment. Here we demonstrate that protamine and its 14-22 amino acid long fragments overcome the neurite outgrowth inhibition by chondroitin sulfate proteoglycans (CSPGs) that are generally regarded as major inhibitors of regenerative neurite growth after injuries of the adult central nervous system (CNS). Since the full-length protamine was found to have toxic effects on neuronal cells we used the in vitro neurite outgrowth assay to select a protamine fragment that retains the activity to overcome the neurite outgrowth inhibition on CSPG substrate and ended up in the 14 amino acid fragment, low-molecular weight protamine (LMWP). In contrast to the full-length protamine, LMWP displays very low or no toxicity in our assays in vitro and in vivo. We therefore started studies on LMWP as a possible drug lead in treatment of CNS injuries, such as the spinal cord injury (SCI). LMWP mimicks HB-GAM (heparin-binding growth-associated molecule; pleiotrophin) in that it overcomes the CSPG inhibition on neurite outgrowth in primary CNS neurons in vitro and inhibits binding of protein tyrosine phosphatase (PTP) sigma, an inhibitory receptor in neurite outgrowth, to its CSPG ligand. Furthermore, the chondroitin sulfate (CS) chains of the cell matrix even enhance the LMWP-induced neurite outgrowth on CSPG substrate. In vivo studies using the hemisection and hemicontusion SCI models in mice at the cervical level C5 revealed that LMWP enhances recovery when administered through intracerebroventricular or systemic route. We suggest that LMWP is a promising drug lead to develop therapies for CNS injuries.Peer reviewe

Sähkölukon kokoonpanon standardointi

Opinnäytetyön aiheena oli sähkölukon kokoonpanon standardointi. Standardoinnin tarkoituksena oli luoda kokoonpanoon yhtenäiset työskentelymenetelmät ja sen myötä parantaa kokoonpanon tuottavuutta. Menetelmäkehitystyö tehtiin tuotannossa jo pitkään olleeseen volyymituotteeseen. Menetelmäkehityksen toteuttaminen aloitettiin perehtymällä aluksi kokoonpanon lähtötilanteeseen ja senhetkiseen työohjeistukseen. Lähtötilanne analysoitiin ottamalla kokoonpanotyöstä videomateriaalia, sekä sen ohella perehdyttiin kokoonpano-ohjeeseen. Suunnittelun jälkeen uutta työmenetelmää lähdettiin etsimään kokeilemalla tuotteelle erilaisia kokoonpanojärjestyksiä. Standardoinnin tuloksena kokoonpanoon saatiin yhtenäiset työskentelymenetelmät sekä työpisteet. Työ dokumentoitiin tekemällä uusi kokoonpano-ohje sekä lisäksi kokoonpanotyöstä kuvattiin opastusvideo. Uuden kokoonpanojärjestyksen myötä toimeksiantajan asettama 5 %:n aikasäästö tuotteen loppukokoonpanossa ylitettiin. Koska opinnäytetyö sisältää yrityksen toiminnalle tärkeää tuotantoteknistä materiaalia, siitä tehtiin toimeksiantajan toiveesta erillinen lyhennetty julkinen versio.The topic of this thesis was to standardize an electric lock assembly. The purpose of standardization was to get more uniform working methods and that way to improve productivity. Production development was made to a product that was already in production. Production development was started by studying the initial situation and work instructions. The initial situation was analyzed by getting video footage of the assembly work and also studying assembling instructions. After planning, the new working methods were found by testing different assembling orders. Uniform working methods and working stations were the result of the standardization work. The work was documented by making new assembly instructions and an additional tutorial video. With standardized working methods productivity of the assembling increased over 5%, which was a minimum target set by the client. Because this thesis includes important material of the operation of the company, an additional, separate public version was made of this thesis

Opetuksen kehittäminen autoalan ammatillisessa koulutuksessa

Opinnäytetyön tavoitteena on selvittää autoalan ammatillisessa koulutuksessa opiskelevien opiskelijoiden oppimistyylit ja oppimistavat. Selvityksen kohteena on Oulun seudun ammattiopiston, Haukiputaan yksikön autoalan perustutkintolaiset, jotka ovat aloittaneet opintonsa syksyllä 2018. Selvitystyö koettiin tarpeelliseksi koska haluttiin tietää, millaiset oppimisympäristöt ja opetusmenetelmät tukevat opiskelijoiden oppimistyylejä sekä miellejärjestelmään liittyvää oppimistapaa. Näiden tarvekohtaannolla on positiivinen vaikutus opiskelumotivaatioon ja tätä kautta opiskeluista suoriutumiseen. Lähestymistapa tässä opinnäytetyössä on tapaustutkimus. Työn perustana käytettiin aiempaa kirjallisuus- ja tutkimustietoutta. Tapaustutkimus soveltui parhaiten lähestymistavaksi, koska tutkimuksen tavoitteena oli saada enemmän syvällistä tietoa opiskelijoista ja antaa kehittämisideoita. Kehittämisideoita löydettiin tutkimalla oppilasainesta kyselytutkimuksen keinoin. Kyselyyn vastattiin internetpohjaisella kyselylomakkeella Haukiputaan yksikön toimintaympäristössä. Kyselylomakkeella saatiin paljon tietoa, jota voidaan hyödyntää henkilökohtaisen osaamisen kehittämissuunnitelman tekovaiheessa. Teoreettinen viitekehys on oppiminen, näkökulmana oppimistyylit sekä miellejärjestelmät. Kehittämistyön tuloksena löydettiin oppimistyylin ja oppimistavan yhdistelmä, joka suosituimpana antaa suuntaa oppimisympäristöjen kehittämiselle. Opiskelijat haluavat oppia toiminnan kautta. Toiminnalliset oppimisympäristöt, visuaalisuuden korostaminen ja mahdollisuus itsenäisempään opiskeluun etenkin teoriaopinnoissa korostuivat tuloksista. Näissä voitaisiin tehdä suorituksia myös ilman opettajaa, ohjeen tai videoidun mallin avustuksella. Tulevaisuudessa on suositeltavaa kokeilla oppimistyyleihin perustuvaa opetusta, mutta tällöin kouluttajan oppimistyylin tulee olla sama kuin opiskelijoiden. Tutkimuksen avulla saaduista tuloksista on tehty yhteenveto. Tulevaisuudessa pyritään antamaan mahdollisuus jokaiselle oppijalle oppimistyylinsä mukaiseen oppimisympäristöön ja myöhemmin kykyjensä mukaiseen osaamiseen. Tässä työssä laadittua kyselyä voidaan hyödyntää myös jatkossa henkilökohtaisen osaamisen kehittämissuunnitelman eli HOKSin suunnittelussa

Ikääntyneiden terveydentilaa kartoittavat kotikäynnit : pilottihanke Lahden keskustan alueella

Opinnäytetyö on osa Lahden kaupungin vanhusten avopalveluiden ja Lahden ammattikorkeakoulun yhteistyössä toteutettua Kartoittavat kotikäynnit- hanketta. Kohderyhmänä olivat vuonna 1930 syntyneet lahtelaiset, jotka eivät kuulu palveluiden piiriin. Kotikäynneillä kartoitettiin ikääntyneiden toimintakykyä, terveydentilaa ja palveluntarvetta. Haastateltavia henkilöitä oli yhteensä 69. Opinnäytetyön tarkoituksena on selvittää, mitkä tekijät vaikuttavat kotona asuvien 1930 syntyneiden ikääntyneiden selviytymiseen päivittäisissä toiminnoissa. Opinnäytetyön tarkoituksena oli myös arvioida Ikääntyneiden kartoittavat kotikäynnit- hankkeen toteutustapaa ja nostaa esille aikasempien tutkimusten tuloksia soveltaen kehittämisajatuksia kotikäyntien toteutukseen liittyen. Opinnäytetyö painottuu hankkeessa valmiiksi kerätyn aineiston analysointiin. Ensisijaisesti opinnäytetyö on kvantitatiivinen tutkimus, jossa aineistonkeruussa käytettiin strukturoitua haastattelulomaketta. Laaja-alaisen käsittelyn saavuttamiseksi tutkimuksessa käytettiin myös triangulaatiota, jossa yhdistyy sekä määrällinen että laadullinen tutkimusmenetelmä. Määrällinen aineisto analysoitiin SPSS Statistics 19- ohjelmaa käyttäen ja laadullisen aineiston analysoinnissa käytettiin deduktiivista sisällönanalyysiä. Tämän opinnäytetyön tuloksista käy ilmi, että lahtelaiset ikääntyneet kokevat pääosin terveydentilansa melko hyväksi ja selviävät päivittäisitä toiminnoista itsenäisesti tai omaisten tuella. Lisäksi he kokivat tarvitsevansa lisätietoa itsenäisen asumisen tukemismahdollisuuksista. Työssä tuodaan esille myös hankkeen jatkokehitysehdotuksia ja – keinoja, joilla tulevaisuudessa voidaan parantaa kartoittavien kotikäyntien luotettavuutta ja kuinka tehdä toiminnasta enemmän ikääntyneiden terveyttä edistävää.This thesis is a part Preventive home visits project carried out jointly by the department of home care services for elderly people of the City of Lahti and Lahti University of Applied Sciences. The target group was Lahti residents born in 1930 and who are not presently covered by the services. Functional capability, state of health, and need for services were studied during the visits to elderly people’s homes. Altogether 69 persons were interviewed. An objective of the thesis was to find out what are the factors which affect every day tasks of 81-year-olds living at private homes. Another objective was to evaluate implementation of Preventive home visits project and to make suggestions for further improvements combining the results from earlier studies. In the data evaluation phase the emphasis was on the pre-collected material. Triangulation method was chosen to analyze the data. The thesis is primarily quantitative study using carefully structured interview form in data collection. Quantitative material was analyzed by using SPSS Statistics 19- programme. The results of this study indicate that the majority of the elderly residents of Lahti consider their state of health fair and manage everyday tasks on their own or with help of their relatives. On the other hand they need more information about support alternatives for independent living. The thesis proposes also ideas for further development of the project and means to improve the reliability of the project in the future, and how to direct the actions to improve the preventive health care of elderly people

Spinal versus brain microglial and macrophage activation traits determine the differential neuroinflammatory responses and analgesic effect of minocycline in chronic neuropathic pain

Substantial evidence indicates involvement of microglia/macrophages in chronic neuropathic pain. However, the temporal-spatial features of microglial/macrophage activation and their pain-bound roles remain elusive. Here, we evaluated microglia/macrophages and the subtypes in the lumbar spinal cord (SC) and prefrontal cortex (PFC), and analgesic-anxiolytic effect of minocycline at different stages following spared nerve injury (SNI) in rats. While SNI enhanced the number of spinal microglia/macrophages since post-operative day (POD)3, pro-inflammatory MHCII+ spinal microglia/macrophages were unexpectedly less abundant in SNI rats than shams on POD21. By contrast, less abundant anti-inflammatory CD172a (SIRPα)+ microglia/macrophages were found in the PFC of SNI rats. Interestingly in naïve rats, microglial/macrophage expression of CD11b/c, MHCII and MHCII+/CD172a+ ratio were higher in the SC than the cortex. Consistently, multiple immune genes involved in anti-inflammation, phagocytosis, complement activation and M2 microglial/macrophage polarization were upregulated in the spinal dorsal horn and dorsal root ganglia but downregulated in the PFC of SNI rats. Furthermore, daily intrathecal minocycline treatment starting from POD0 for two weeks alleviated mechanical allodynia most robustly before POD3 and attenuated anxiety on POD9. Although minocycline dampened spinal MHCII+ microglia/macrophages until POD13, it failed to do so on cortical microglia/macrophages, indicating that dampening only spinal inflammation may not be enough to alleviate centralized pain at chronic stage. Taken together, our data provide the first evidence that basal microglial/macrophage traits underlie differential region-specific responses to SNI and minocycline treatment, and suggest that drug treatment efficiently targeting not only spinal but also brain inflammation may be more effective in treating chronic neuropathic pain.Peer reviewe

Salivary and serum haptoglobin, adenosine deaminase, and immunoglobulin G in growing pigs

Abstract Background Identification of animals in need of medical treatment is important in porcine health management, where analytical samples applicable at farm level could be utilized. Several biomarkers are measurable in saliva, which is less stressful to collect than blood. Saliva sampling is easy to learn and repeatable, making it suitable for monitoring purposes. Previous research suggests that porcine health biomarkers are dependent on production stage and gender, and that combining biomarkers improves diagnostic sensitivity. However, proper monitoring of biomarkers during the complete production cycle has not been studied. We aimed to describe the dynamics of salivary and serum haptoglobin (Hp), adenosine deaminase (ADA), and immunoglobulin G (IgG) in four production stages (suckling, early growing, late growing, finishing), on commercial Finnish pig farms using a total of 117 piglets. The relationship between gender and biomarker dynamics was investigated, as well as the relationships between these biomarkers in saliva and serum. Results The highest salivary concentrations of Hp, ADA and IgG were measured in suckling piglets. The differences between production stages were generally larger in saliva than for the corresponding serum biomarkers. All correlation coefficients between salivary biomarkers were positive in each production stage and the strength of the correlation varied from 0.245 to 0.762. No similar trend was observed regarding correlation coefficients either between serum biomarkers or between salivary and serum biomarkers. Gender was associated with some biomarker concentrations. Conclusions The biomarker dynamics supported previous findings that collection of analytical samples should be conducted in age-matched populations. Positive and even strong relationships between salivary biomarkers indicate the potential to use especially saliva for health monitoring. Our results also suggest the importance of considering gender effects when assessing some salivary or serum biomarkers